Idiopathic pulmonary fibrosis (IPF) is an illness characterized by progressive decline in lung function and premature death from respiratory failure. There is currently no effective therapy for this disease and the study of new therapeutic options is hampered by our inability to predict patients at risk for clinical deterioration. Fibrocytes are a novel population of bone marrow-derived circulating progenitor cells that have been shown to traffic to the lungs and contribute to fibrosis in animal models of pulmonary fibrosis, and whose numbers correlate with the degree of fibrosis and with survival in human pulmonary fibrosis. Our broad, long-term objective is to understand the contribution of fibrocytes to human pulmonary fibrosis and to target this pathological mechanism as a therapeutic modality. Our preliminary data show that: 1) as compared to healthy controls, patients with fibrotic interstitial lung disease have markedly increased levels of the fibrocyte-attracting chemokine, CXCL12, in both the lungs and plasma, which is associated with a marked elevation in the number of peripheral blood and lung fibrocytes; 2) patients with Hermansky-Pudlak syndrome, a genetic disorder that universally results in pulmonary fibrosis in the 3rd decade of life, have a similar expansion of the circulating fibrocyte pool; 3) The elevation of circulating fibrocyte count is an independent predictor of death in IPF; 4) CXCR4 is the major chemokine receptor expressed on human fibrocytes, and its expression is down-regulated by the mTOR inhibitor, sirolimus; and 5) in an animal model of pulmonary fibrosis, administration of sirolimus results in reduced number of blood and lung fibrocytes as well as reduced lung fibrosis. Our overall hypothesis is that in patients with pulmonary fibrosis, 1) the number and/or phenotype of circulating fibrocytes identify patients at risk of disease progression before the progression is detectable clinically, and 2) therapy with the mTOR inhibitor, sirolimus, reduces the number of circulating fibrocytes. We propose to test this hypothesis under the following specific aims: 1) To determine the predictive value of the number and phenotype of circulating fibrocytes for development and progression of pulmonary fibrosis in a cohort of patients with Hermansky-Pudlak syndrome. 2) To serially correlate the number and phenotype of circulating fibrocytes to conventional indices of disease severity in patients with idiopathic pulmonary fibrosis. 3) To perform a short-term pilot trial of the mTOR inhibitor, sirolimus, in patients with IPF to determine its effect on the number and phenotype of circulating fibrocytes. The significance of the proposed studies is that they have the potential to identify a novel biomarker to predict disease progression in IPF, and to lay the groundwork for a therapy for this illness that targets fibrocytes. PUBLIC HEALTH RELEVANCE: Idiopathic pulmonary fibrosis is progressive lung disease that typically results in death from respiratory failure within 3 years of diagnosis, and for which there is no effective treatment. Fibrocytes are a population of blood cells that, according to several lines of evidence, may be involved in damaging the lung in this illness. The proposed studies are relevant to public health in that they have the potential to define the number of these cells in the blood as a novel marker to identify patients with this illness who are at risk of deterioration, so that they can be targeted for testing new treatments. In addition, we propose to perform a small study of an existing drug in this illness, with the aim of targeting these cells therapeutically.